Pyrazolidine-3,5-dione derivatives as potent non-steroidal agonists of farnesoid X receptor: Virtual screening, synthesis, and biological evaluation

Article abstract of DOI:10.1016/j.bmcl.2008.09.027

The identification of a novel pyrazolidine-3,5-dione based scaffold hit compound as Farnesoid X receptor (FXR) partial or full agonist has been accomplished by means of virtual screening techniques. A series of pyrazolidine-3,5-dione derivatives (1a-u and

Full text of DOI:10.1016/j.bmcl.2008.09.027

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5497–5502
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Pyrazolidine-3,5-dione derivatives as potent non-steroidal agonists
of farnesoid X receptor: Virtual screening, synthesis, and biological evaluation
Guanghui Deng a, , Weihua Li a, , Jianhua Shen a, , Hualiang Jiang a,b, Kaixian Chen a, Hong Liu a,
*
*
a Drug Discovery and Design Centre, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Graduate School of the Chinese Academy of Sciences,
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
b School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 May 2008
Revised 2 July 2008
Accepted 5 September 2008
Available online 10 September 2008
The identification of a novel pyrazolidine-3,5-dione based scaffold hit compound as Farnesoid X receptor
(FXR) partial or full agonist has been accomplished by means of virtual screening techniques. A series of
pyrazolidine-3,5-dione derivatives (1a–u and 7) was designed, synthesized, and evaluated by a cell-based
luciferase transactivation assay for their agonistic activities against FXR. Most of them showed agonistic
potencies and 10 of them (1a, 1b, 1d–f, 1j, 1n, 1t, 5b, and 7) exhibited lower EC50 values than the refer-
ence drug CDCA. Molecular modeling studies for the representative compounds 1a, 1d, 1f, 1j, 1n, 1u, 5b,
and 7 were also presented. The novel structural scaffold has provided a new direction for finding potent and selec-
tive FXR partial and full agonists (referred to as ‘selective bile acid receptor modulators’, SBARMs).
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Farnesoid X receptor
Pyrazolidine-3,5-dione
Virtual screening
Farnesoid X receptor (FXR) is a member of the superfamily of
nuclear receptors and is expressed in the liver and intestine as well
as other cholesterol-rich tissues such as the adrenal gland.1 Three
research groups independently identified FXR as a nuclear receptor
for bile acids in 1999.2–4 As a sensor of bile acids, FXR regulates the
expression of several target genes involved in the bile acids biosyn-
thesis and transport. In the liver, FXR indirectly represses the
expression of CYP7A1, a key enzyme that catalyzes the rate-limit-
ing step in the conversion of cholesterol into the bile acids.5 Acti-
vated FXR also positively regulates the expression of genes that
encoded proteins in the transport of bile acids, including the intes-
tinal bile acid-binding protein (IBABP) and bile salt export pump
(BSEP).6,7 Furthermore, FXR is involved in processes such as glu-
cose utilization, inflammation, and cancer deriving from the intri-
cate network of interactions concerning bile acids metabolism.8
Thus, FXR is emerging as a particular target for the promising po-
tential treatment of hyperlipidemia, cholelithiasis, cholestasis,
and diabetes mellitus.9,10
(UDCA) deserved more than 20 years of research activity culminat-
ing with the clinical use in the treatment of gallbladder stones and
cholestatic liver diseases.8 Based on structural modification of
CDCA, Pellicciari et al.11 synthesized 6
a-ethyl-chenodeoxycholic
acid (6ECDCA, INT-747) as a highly potent FXR full agonist and is
launching phase II trial for the potential treatment of liver diseases,
and type 2 diabetes. Upon the side chain modification of CDCA,
they also presented some 3a,7a-dihydroxy-24-nor-5b-cholan-23-
amine derivatives as partial agonists against FXR.12 GW4064 was
identified as the first non-steroidal FXR agonist endowed with
nanomolar potency through high-throughput screening and com-
binatorial chemistry approach.13 High-throughput screening com-
bined with optimization of benzopyran-based combinatorial
library result in the discovery of fexaramine, another structurally
diverse non-steroidal FXR agonist.14 However, although a few dif-
ferent types of synthetic molecular agonist of FXR have been dis-
covered, no drug active against FXR has been approved by the
FDA so far. Therefore, it is a great challenge to discover and develop
novel compounds as FXR modulators not only for the potential
treatment of metabolic syndrome, but also for the etiology re-
search of human disease.15,16
Over the past few years, many efforts have been dedicated to
seek highly potent modulators such as full and partial FXR ago-
nists, which are also referred to as ‘selective bile acid receptor
modulators’, SBARMs. A partial agonist relative to a full agonist is
defined as a ligand that induces a submaximal response even at full
receptor occupancy. Bile acids are the endogenous agonists for FXR,
such as chenodeoxycholic (CDCA, Fig. 1) and ursodeoxycholic acid
Within our efforts in the study of new FXR agonists, we set up a
virtual screening17 protocol based on crystal structures of FXR in
complex with agonists. A series of screening methods including
docking, consensus scoring, FlexX scoring, and drug-likeness anal-
ysis were used to improve the hit rate.18,19 By screening of molec-
ular database SPECS (http://www.specs.net) and being followed by
biological evaluation, 1a was identified with an EC50 value of
* Corresponding authors. Tel.: +86 21 50807042; fax: +86 21 50807088.
E-mail address: hliu@mail.shcnc.ac.cn (H. Liu).
5.15 lM for activating FXR in a cell-based luciferase transactiva-
These authors contributed equally to this work.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.09.027

5498
G. Deng et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5497–5502
O
O
OH
H
OH
HO
OH
HO
OH
CDCA
H
6-ECDCA
O
O
N
N
O
Cl
O
Cl
O
N
HO
Cl
GW-4064
O
Fexaramine
H
N
2
N
B
5
O
O
O 3
A
1a
Figure 1. Known FXR agonists and our hit compound 1a.
tion assay. Using the hit 1a as the benchmark compound, a series of
novel pyrazolidine-3,5-dione derivatives was designed, synthe-
sized, and evaluated by a cell-based luciferase transactivation as-
say for their agonistic activities against FXR. Molecular modeling
studies were also carried out to investigate their interactions with
FXR.
system. In contrast to Dock 4.0, FlexX utilizes an adapted Böhm
empirical function to evaluate the ligand–receptor interactions.
Those compounds with score ranked top 10% were remained in
the hit lists. At this stage, approximately 220 molecules were cho-
sen for further visual inspection and drug-likeness analysis. At the
final stage, we restored the selected 220 molecules into the binding
pocket of FXR one by one to inspect their locations. The Lipinski’s
‘rule of 5’.23 and an additional Chemistry Space Filter24 as filters
for drug-likeness analysis were applied on all retrieved compounds
and the molecules that violated these rules were eliminated. Fol-
lowing the above steps, 73 molecules were selected and purchased
from the SPECS Company and then evaluated by a cell-based lucif-
erase transactivation assay.
The FXR model used for virtual docking was taken from the
coordinate of FXR in complex with fexaramine (PDB entry1OSH)
and the missing coordinates of residues from 271 to 285 were
reconstructed based on the corresponding coordinates in the crys-
tal structure of rat FXR-6ECDCA complex (PDB entry 1OSV) using
Sybyl version 6.8 (Tripos Inc., 2000). All ligands and ions were re-
moved from the crystal structure of FXR complexes and the FXR
model was added with polar hydrogen and Kollman-united-atom
charges. A database of over 120,000 compounds (SPECS collection)
was assigned with Gasteiger–Marsili charges and was initially
Among the 73 molecules, compound 1a, characterized by a
completely new scaffold (Fig. 1), showed a moderate agonistic
activity (EC50 = 5.15 lM) and was therefore chosen as the starting
screened using the paralleled version of Dock 4.020,21 modified by
point for further structural optimization. Using different substi-
tuted benzoyl groups of 1a, compounds 1b–e were synthesized
(Table 1). Substituting on the N1 and N2 positions of the pyrazoli-
dine-3,5-dione core, compounds 1d–l were obtained. Changing 3-
benzyloxy group with 4-benzyloxy group, compounds 1m–u were
obtained along with phenyl, bezoyl or furoyl substitution on N1
position of pyrazolidine-3,5-dione core. While disubstitution on
the N1 and N2 position with phenyl group, replacing the benzyloxy
group with NO2 group and disubstitution on the N1 and N2 posi-
tions, compound 7 was achieved. The synthesis of this class of pyr-
azolidine-3,5-dione derivatives is outlined in Scheme 1. Aldol
addition of substituted benzaldehyde 2a and 2b with diethyl mal-
onate 3 which were catalyzed by acetic acid and piperizine under
refluxing, afforded compounds 4a and 4b. Phenolic hydroxyl
groups of 4a and 4b were alkylated by benzyl chlorides or bro-
mides to produce the desired compounds 5a–e by the use of micro-
waves in sealed tube. Condensation of 5a–e with various
substituted hydrazine in the presence of NaOEt and EtOH afforded
0
our laboratory. Residues around the ligand at radius 5 ÅA in the
FXR–fexaramine structure were selected to construct the grids of
docking screening. During the execution of Dock 4.0 program, 25
configurations per ligand building a cycle and 50 maximum anchor
orientations were used in the anchor-first docking algorithm. All
docked configurations were energy minimized using 100 maxi-
mum iterations and one minimization cycle. At this stage, the mol-
ecules ranked top 5000 in docking energy were selected for further
analysis. At the second stage, CScore (Consensus Score) module in
Sybyl6.8 was utilized to re-score the selected molecules. CScore
integrates five popular scoring functions for ranking the affinity
of ligands bound in the active site of a receptor. Those molecules
with CScore above 3 were filtered out. Thus, approximately 2800
molecules were removed after this filter. The remaining 2200 mol-
ecules were chosen for further modeling and calculation using
FlexX module in Sybyl 6.8. The FlexX program22 considers both
the torsion angle flexible and the conformational flexibility of ring

G. Deng et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5497–5502
5499
Table 1
Structures and agonistic activities against FXR in a cell-based luciferase transactivation assay of pyrazolidine-3,5-dione derivatives in terms of fold activation at 10 lM
3
R3
R2
N
N
B
1
O
R1
O
O
A
a
Compound
R1
R2
R3
Substituted position of Ring A
Fold-activity at 10 lM
1a
1b
1c
1d
1e
1f
1g
1h
1i
3-CH3
3-F
Phenyl
Phenyl
Phenyl
Phenyl
2-Nitrophenyl
4-Fluorobenzoyl
4-Methoxylbenzoyl
Naphthalene-1-carbonyl
Thiophene-1-carbonyl
Pyridine-4-carbonyl
CH3
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
H
H
H
meta
meta
meta
meta
meta
meta
meta
meta
meta
meta
meta
meta
para
para
para
para
para
para
para
para
para
2.88 0.12
3.17 0.06
3.04 0.06
3.22 0.18
3.19 0.01
2.98 0.24
2.32 0.71
2.27 0.42
2.54 0.36
3.28 0.22
2.61 0.39
2.41 0.10
2.34 0.02
3.15 0.13
2.16 0.48
2.48 0.00
2.25 0.06
2.42 0.15
2.15 0.46
2.93 0.37
7.97 1.35
3-CF3
4-CF3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
H
H
H
H
H
H
H
H
H
1j
1k
1l
H
1m
1n
1o
1p
1q
1r
1s
1t
Phenyl
Benzoyl
2-Chlorobenzoyl
4-Chlorobenzoyl
4-Bromobenzoyl
4-Methoxylbenzoyl
Naphthalene-1-carbonyl
2-Furoyl
1u
Phenyl
Phenyl
O
O
5a
5b
7
2.32 0.29
O
O
O
O
O
O
O
2.80 0.08
O
N
N
3.15 0.14
O
O
NO2
O
H
OH
CDCA
10.98 1.61
HO
OH
H
a
Values were calculated according to solvents control (as 1-fold). Each data point is the average of triplicate assays. Each experiment was repeated three times.
compounds 1a–u in 30 min via microwave-assisted reaction. Com-
pound 7 was prepared in the similar procedures without the
phenolic hydroxyl-alkylation step.
All derivatives (1a–u and 7, Table 1) and the precursors 5a and
5b were evaluated by a cell-based luciferase transactivation as-
say25 (for details, see Supplementary data) for their agonistic activ-

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G. Deng et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5497–5502
O
O
O
O
a
O
1
O
O
R
+
O
O
1
R = OH
OH
3
2a-c
1
a
R = NO
2
4a-b
b
O
O
O
O
O
O
NO
2
O
O
2
R
6
O
c
5a-e
c
4
N
N
R
N
3
R
N
O
O
O
2
R
NO
2
O
O
1a-u
7
Scheme 1. Synthetic routes of compounds 1a–u, 5a, 5b, and 7. Reagents and conditions: (a) HOAc, piperizine, EtOH, reflux, overnight; (b) K2CO3, EtOH, various benzyl
chloride, MW, 100 °C, 10 min, sealed tube; (c) NaOEt, EtOH, MW, 140 °C, 30 min, sealed tube.
ities against FXR, using CDCA as the reference drug. As shown in
Table 1, all the compounds showed agonistic activities against
Table 2
Determination of EC50 values of selected compounds
FXR at 10
to 7.97-fold (1u). Many of them (10 out of 24) had agonistic activ-
ities higher than that of the initial lead 1a (2.88-fold at 10 M,
EC50 = 5.15 M). Introducing electron-withdrawing group 3-F, 3-
CF3, or 4-CF3 to the benzyloxy group (1b–d) resulted in improved
activity to 3.17-, 3.04-, and 3.22-fold at 10 M, respectively. When
the N1 substituent was changed from phenyl group into 2-nitro-
phenyl group, the activity was improved from 2.88- to 3.19-fold
at 10 lM (1e). While, replacing N1 substituent with various acyl
groups led to fold-activity ranging from 2.27- to 3.28-fold (1f–j).
lM, with the fold activation range from 2.15-fold (1s)
Compound
EC50 (lM)
1a
1b
1c
1d
1e
1f
1j
1n
1t
5.15
4.79
6.92
2.04
5.37
1.86
2.40
3.98
3.31
6.31
6.17
4.27
6.31
l
l
l
1u
5b
7
The N1,N2-dimethyl-substituted derivative (1k, 2.61-fold at
10 lM) or N1,N2-unsubstituted derivative(1l, 2.41-fold at 10 lM)
CDCA
showed reduced agonistic activity. Little change in activity was ob-
served by meta- or para-substitution on the benzyl ring A (1m–t).
N1,N2-Diphenyl-substituted pyrazolidine-3,5-dione core (1u)
than that of CDCA (Table 2). Compound 1f (EC50 = 1.86 lM) de-
showed the most potent fold activation (7.97-fold at 10 lM)
served the most potent agonistic activity. As illustrated in Figure
2, compounds1f, 1d, 1j, and 1u induced higher activation than that
among all the synthesized compounds. Surprisingly, the precursor
compounds with diethyl malonate moiety instead of pyrazolidine-
3,5-dione core along with 4-benzyloxy moiety (5b, 2.80-fold at
of CDCA at low concentration (below 5
1j induced a submaximal response compared with CDCA (approx-
imate 3- vs 10.98-fold at 10 M). This finding suggested that 1d, 1f,
lM). However, 1d, 1f, and
10
along with 3-(30-methyl)-benzyloxy moiety (5a) showed less po-
tent activity (2.32-fold at 10 M). Another interesting finding
was that the short skeleton compound with 3-NO2 instead of moi-
ety 3-benzyloxy moiety (7, 3.15-fold at 10 M) exhibited positive
lM) exhibited positive agonistic activity while the same class
l
and 1j may act as partial agonists of FXR in this experimental set-
ting. In addition, 1u exhibits a similar maximal response compared
with CDCA (7.97 1.35- vs 10.98 1.61-fold at 10 lM) which sug-
l
l
gest that in this particular experimental setting 1u acts as a full
agonistic activity and was even stronger than that of 1a.
agonist.
To determine the exact potency of the compounds that demon-
strated significant agonistic activities against FXR, 11 compounds
were selected for further investigation in concentration–response
studies, and the results are summarized in Table 2. All these com-
pounds concentration-dependently activated FXR and showed
prominent agonistic activities with concentration at half-maximal
stimulation (EC50) values ranging from 1.86 to 6.92 lM. Among
them, seven compounds deserved higher potency than that of
the initial hit 1a and 10 compounds showed higher EC50 values
Molecular modeling experiments were carried out to investi-
gate the binding interactions between compounds (1a, 1d, 1f, 1j,
1n, 1u, 5b, and 7) and FXR, which aimed to provide the molecular
basis for further structural optimization (for details, see Supple-
mentary data). The crystal structure of human FXR–fexaramine
complex reveals that the ligand binding pocket is hydrophobic,
long and narrow (for details, see Supplementary data). Figure 3A
shows the interaction modes of four potent partial agonists (com-

G. Deng et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5497–5502
5501
into the deeper hydrophobic binding pocket of FXR. This may in
part explain the higher agonistic activities of 1f and 1j against
FXR when compared to 1a. Compared with the above compounds
1a, 1d, 1f, and 1j, 1n has the para-substitution on the benzyl ring
A. Because the binding pocket is hydrophobic, long and narrow,
this different substitution results in a different binding mode
(Fig. 3B) with the meta-substitution of the ring A (i.e., 1f and 1j).
The para-substitution leads to an extended conformation of the
ether oxygen group. This change leads to the loss of the hydrogen
bonds formed between the ether oxygen atom and His298 and
Ser336, which was observed in the meta-substituent compounds
(1f and 1j). This may in part account for the lower potency when
compared to 1f and 1j.
In contrast to the above five compounds, the full agonist 1u has a
distinct structure. This implies 1u may have different binding mode
with the above compounds. This idea was supported by the binding
conformations obtained by molecular docking. Compared to the
above compounds, the two N atoms of pyrazolidine-3,5-dione core
of 1u is disubstituted by phenyl group. These two phenyl groups
form an expanded conformation, and thereby can not extend into
the deep binding pocket of FXR. One of carbonyl groups in pyrazoli-
dine-3,5-dione core forms a hydrogen bond with His298, while the
two phenyl rings form hydrophobic contacts with Met294,
Phe340, Phe370, Met369, Leu352, and Ile356, as shown inFigure 3C.
Compounds 5b and 7 also showed higher potency than CDCA.
However, these two compounds have different structural sketch
from the above four compounds (1a, 1d, 1f, and 1j). Compared with
Figure 2. Concentration–response studies of four representative synthesized
compounds 1f, 1d, 1j, and 1u using CDCA as a control.
pounds 1a, 1d, 1f, and 1j) with FXR ligand binding pocket. As seen
in Figure 3A, these four compounds have similar binding modes.
The pyrazolidine-3,5-dione core occupies the deep hydrophobic
area, while the substituted N1 moiety points to the receptor’s ‘back
door’,12 localized between loops H1–H2 and H5–H6. The pyrazoli-
dine-3,5-dione core interacts with the protein residues through
two hydrogen bonds with Leu291 from helix 3 and with Tyr365
from helix 7 respectively. In contrast, the O atom of the ether skel-
eton forms hydrogen bonding both with His298 from helix 3 and
Ser336 from helix 5. At the same time, the two phenyl rings A
and B of the agonists interact with the receptor via van der Waals
interaction. The trifluoromethyl group of 1d, on one hand, forms
strong hydrophobic interaction with the residues from helix 2;
on the other hand, it points to the space between helices 2 and 5
and has no steric hinder with residues from helix 5. This may con-
tribute to its lower EC50 value than 1a. Compared with 1a, the addi-
tional carbonyl group of the N1 substituents of 1f and 1j increases
the length of these two compounds, which resulted in an extension
pyrazolidine-3,5-dione derivative 1t (EC50 = 3.31
lM), compound
5b was a precursor for the synthesis of 1t with diethyl malonate
moiety instead of pyrazolidine-3,5-dione core. These two ethyl es-
ter groups form an extended conformation, which results in a
bulky volume when compared with compounds 1t. For this reason,
this moiety of compound 5b could not bind at the deep pocket
formed by helix 12, 11, and 3, since the pocket inside the fold is
too narrow and long to accommodate the groups of large size.
From Figure 3D, compound 5b forms two hydrogen bonds with
His298 and Ser336 at one of its ethyl ester groups. The other ethyl
ester group form hydrophobic interactions with Phe340, Phe370,
Met369, Leu352, and Ile356. The benzyloxy moiety of compound
5b extends into the deep binding pocket. This binding orientation
is just contrary to that of aforementioned four compounds. In con-
trast with compound 1a–u, compound 7 is shorter in length. Like
Figure 3. Close view of binding modes of high potent compounds in the binding pocket of human FXR (PDB code: 1OSH). Hydrogen bonds are represented by green dotted
lines. Important residues are labeled. (A) compound 1a (green), 1d (yellow), 1f (pink), and 1j (cyan); (B) compound 1n; (C) compound 1u; (D) compound 5b; (E) binding mode
1 of compound 7; (F) binding mode 2 of compound 7.

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G. Deng et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5497–5502
compound 1u, these two phenyl groups also form an extended
conformation. The docking results proposed two distinct binding
modes existed for compound 7, as shown in Figure 3E and F. In
both binding modes, one of carbonyl groups in pyrazolidine-3,5-
dione core forms a hydrogen bond with His298. However, the ori-
entation of nitrobenzyl group differs a lot. In binding mode Figure
3E, the nitrobenzyl group binds in the deep pocket of FXR, whereas
in binding mode Figure 3F, the same group points to the ‘back
door’. Regardless of the distinct binding modes, one of N-phenyl
group on pyrazolidine-3,5-dione core points to the vacuum and
forms hydrophobic contacts with Met294, Phe340, Phe370,
Met369, Leu352, and Ile356. Although only one hydrogen bond
forms between compound 7 and ligand binding pocket, the strong
hydrophobic interactions formed by its phenyl ring compensates in
part the loss in hydrogen bonding interaction. This may account for
the high potency of compound 7.
In summary, a novel hit compound (1a) was discovered by
means of virtual screening techniques. Starting from the hit, a ser-
ies of compounds have been rapidly generated by microwave tech-
niques and evaluated by a cell-based luciferase transactivation
assay with the aim of identifying potential FXR agonists endowed
with positive pharmacological profile in the treatment of metabolic
diseases. Among all the tested compounds, 12 compounds exhib-
ited potent partial or full agonistic activities compared to that of
the reference drug (CDCA), with EC50 values between 1.86 and
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We gratefully acknowledge financial support from the State Key
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20721003), and the 863 Hi-Tech Program of China (Grant
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Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2008.09.027.